Pharmacokinetics and Metabolism of Radiolabelled SNI-2011, a Novel Muscarinic Receptor Agonist, in Healthy Volunteers

The pharmacokinetics and metabolism of SNI-2011 ((±)-cis-2-methylspiro[1,3-oxathiolane-5,3’-quinuclidine]monohydrochloride hemihydrate, cevimeline, CAS 153504-70-2), a novel muscarinic acetylcholine receptor agonist developed for the treatment of Sjogren’s syndrome, were investigated in six healthy volunteers after a single oral administration of 14 C-SNI-2011. After administration, plasma concentrations of the radioactivity and SNI-2011 reached to C max at approximately 2 h, and then decreased with t 1/2 of 9 and 4 h, respectively.C max and AUC 0–∞ of the radioactivity in plasma were 2.2 and 5.0 times higher than those of SNI-2011, respectively. The main excretion route of the radioactivity was urine, and 97.3 % of the dose excreted in urine within 168 h, indicating that 14 C-SNI-2011 was completely absorbed. The mean recoveries of the metabolites in urine at 24 h after administration were 16.0 % for SNI-2011, 35.8 % for SNI-2011 trans-sulfoxide (SNI-t-SO), 8.7 % for SNI-2011 cis-sulfoxide, 4.1 % for SNI-2011 N- oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6 % and 7.7 %, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of SNI-2011 and SNI-t-SO, respectively.